The aberrant promoter methylation of BMP3b and BMP6 in malignant pleural mesotheliomas.
Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta superfamily. Recent studies have showed that aberrant methylation of BMP genes is present in several types of human cancer. We examined the expression and methylation status of BMP3b and BMP6 in malignant pleural mesotheliomas (MPMs). The expression status of BMP3b, and BMP6 mRNAs were examined in seven MPM cell lines by RT-PCR assay. The expression of BMP3b was completely suppressed in 2 and partially suppressed in 2 of 7 cell lines and expression of BMP6 was partially suppressed in 2 cell lines. Methylation status of BMP3b in cell lines was determined by methylation-specific assay to find aberrant methylation in 6 cell lines which include 4 cell lines with suppressed BMP3b expression. Partial methylation of BMP6 was found in 2 cell lines whose expression was partially suppressed. Treatment with 5-Aza-dC restored BMP3b expression in methylated cell lines. Next, we examined the methylation status in 57 surgically resected MPM cases and found aberrant methylation of BMP3b in 9 (53%) out of 17 cases from Japan and 3 (8%) of 40 cases from USA and that of BMP6 in 4 (24%) cases from Japan and 12 (30%) cases from USA, showing significant difference in frequency of BMP3b methylation between MPMs of the two countries (P=0.0004). Our study indicated that BMP3b and BMP6 genes were suppressed by DNA methylation and methylation of BMP3b is significantly frequent in Japanese MPMs, suggesting its pathogenic role and the ethnic difference in MPMs.
Kimura
Kentaro
K
Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikata-cho, Okayama, Japan.
Toyooka
Shinichi
S
Tsukuda
Kazunori
K
Yamamoto
Hiromasa
H
Suehisa
Hiroshi
H
Soh
Junichi
J
Otani
Hiroki
H
Kubo
Takafumi
T
Aoe
Keisuke
K
Fujimoto
Nobukazu
N
Kishimoto
Takumi
T
Sano
Yoshifumi
Y
Pass
Harvery I
HI
Date
Hiroshi
H
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D055413:Growth Differentiation Factor 10 / Q000235:genetics*; D006801:Humans; D007564:Japan / Q000208:ethnology; D008654:Mesothelioma / Q000208:ethnology / Q000235:genetics*; D010997:Pleural Neoplasms / Q000208:ethnology / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014481:United States / Q000208:ethnology
C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D004791:Enzyme Inhibitors; C525785:GDF10 protein, human; D055413:Growth Differentiation Factor 10; D012333:RNA, Messenger; D000077209:Decitabine; D001374:Azacitidine